N&#39;-(1-naphthylmethyl)-n3-aminoguanidine and salt thereof



United States Patent ce Patented Apr. 9, 1968 (1) Reacting a compound ofthe formula 3,377,381 SB. N-(1-NAPHTHYLMETHYL)-N -OGUANIDINE AND SALTTHEREOF A1CHn-NHC=NR III Andl' L g Laurent, Q (2311353, assign)! 5 or asalt thereof, with a compound of the formula to American Home ProductsCorporation, New York, N.Y., a corporation of Delaware No Drawing.Continuation of application Ser. No.

370,078, May 25, 1964. This application Aug. 4, 1967, Ser. N0. 658,363Rt IV 2 Claims. (Cl. 260-564) and (2) Reacting a compound of the formulaABSTRACT OF THE DISCLOSURE 1 There are disclosed herein N-o-chlorobenzyl-N -ami- .HN NH C=NH VI noguanidine, 1 o chlombenZy1 Namethy1 Ns amin0 or a salt thereof, w1th a compound of the formulaguanidine, N -o-chlorobenzy1-N -methyl-N -dimethylami- A CH2 NH2 VIInoguanidine, N 'o-bromobenzyl-N -aminoguanidine, N VamethYlbehZYhNLaminowanidihe and 1 wherem A represents (1) anortho-substituted phenyl methy1) N3 amihoguanidihe The compounds of thisgroup, the substitue t of WhlCh 1s a halogen atom or a vention areuseful as antihypertensive agents and methods methyl group (11) anaphthyl group, B represents a f their preparation and use are alsogiven lower alkyl group, desirably containing from 1 to 6 carbon atoms,and preferably methyl, A represents an ortho-substituted phenyl group,the ortho su-bstituent of This application is a continuation of andreplacement Whlch 1s a haIPgeD atom a methyl goup and R1 and for mypresently copending application, Ser. No. 370,078, R2 and R3 Whlch maybethe same or dlfferent each filed May 25, 1964, and allowed on May 9,1967, and now Sent hydmgen atom W a methtil gTOuP- abandone A preferredprocedure accordlng to this inventlon This invention relates to'guanylhydrazines. for preparing compounds of the formula Moreparticularly, my invention relates to ortho sub- R1 R: stitutedbenzylguanylhydrazines and to naphthylmethyl- 1 guanylhydrazines, theircorresponding acid addition salts, II and to the processes by whichthese compounds are pre- N R pared.

The compounds of the invention may be represented by the generalformula: II or salts thereof, comprises, reacting a compound of the H lformula ACH2-NCNN I IR Ra I X SB wherein A represents (i) anortho-substituted phenyl group, the substituent of which is a halogenatom or a 111 methyl group, a p y p; 1, 2 and or a salt thereof, with acompound of the formula R which may be the same or dilferent, eachrepresent R a hydrogen atom or a methyl group. 2 The newguanylhydrazines possess hypotensive prop- RINK-N erties due toselective peripheral sympathetic blockade. R3 IV These properties dependon the presence of a suitable wherein X re presents a halogen atom or amethyl group, ortho substltuent on the nucleus. The compounds exh1b1tand B R, R1, Rzand R3 have the above memioned mean nopara-sympathomlmetic properties, a feature of parmg tlcular advantagewhen as antlhypertfmswe agents A modified procedure for the preparationof the guanyl- They also provlde a sustained effect, making themspehydrazmes of the formula clally useful 1n the treatment of chronichypertenslon. They have the added advantage of not causing localirritation when taken orally. NH V P 5111ta b1e Oral cadmlmsfratlon mayor salts thereof, comprises, the reaction of a compound be prepared bymClIlSlOIT ofthephannacologlcally acceptof the following formula ablesalts of the lnvention with suitable sol1d carriers. B Compositions forinjection may be made by incorpo- 1 rating these salts in suitableliquids. Aqueous solutions NHrNH- VI of the Salts are Preferred. or asalt thereof, with a compound of the formula Broadly speaking, the newguanylhydrazines of the A OH NH invention may be prepared by a processselected from 2 the group of processes consisting of wherein A is asdefined above.

The compounds of the above general Formulae III and V, used as startingmaterials, can be either in the form of their bases or salts. Incarrying out the reaction between Compounds III and IV, water or awatermiscible organic solvent is preferably used, for example,isopropanol. Desirably the reaction is carried out at the boilingtemperature of the solvent. The reaction between Compounds VI and VII isalso preferably carrled out in the presence of an inert solvent, forexample, water, etc. Compound III, either in its base fonm or as a salt,used as a starting material, may conveniently be prepared by reacting anortho-substituted benzylamine hydrochloride, of which the orthosubstituent is defined as above, with a reagent of the class effectiveto convert the, amino group'to a thiourea group. Preferred reagents forthis conversion are sodium isothiocyanate or methyl isothiocyanate. Thethiourea obtained is then reacted with an appropriate alkyl compound,for example, methyl halide, etc., to form the alkylisothiourea startingmaterial. The base form of the alkylisothiourea can be obtained bytreating the salt with alkali. The alkyl group of the alkyl compound,and thus the alkyl substituent of the alkylisothiourea is preferablylower alkyl, those containing from 1 to 6 carbon atoms being preferred.Shown graphically, a typical process for preparing Compound III is:

l Q-orn-und-unn can SCH;

I Q -on.-unc=una 9 wherein R represents hydrogen or methyl, and X ishalogen or methyl.

The Compound VI of the formula IS 81611:; n,N-Nn-eNH, crux NHaNHg=NH1 2wherein Z represents an anion of an acid.

Having thus generally described the invention, it will now be referred.to in greater detail by reference to the following examples,illustrating preferred procedures and reactants, etc.

Example 1.l-o-chlorobenzylthiourea o-Chlorobenzylamine hydrochloride,38.0 g. (0.21 mole) and sodium thiocyanate, 17.0 g. (0.21 mole) wererefluxed for three hours in toluene (250 ml.). The solvent wasevaporated under reduced pressure and the product was crystallized froma mixture of isopropanol and methanol. Yield 21.8 g., M.P. 125l27 C.

Calculated for C I-I CIN S; S, 15.99%. Found: S, 15.99%.

4 Example 2.l-o-chlorobenzyl-Z-rnethylthiourea hydriodidel-o-chlorobenzylthiourea, prepared by Example 1, 21.5 g. (0.11 mole) wasdissolved in acetone (150 ml.) and methyl iodide, 15.6 g. (0.11 mole),was added. The solution was stirred at room temperature for ninetyminutes and the solvent was evaporated under reduced pressure toone-half the original volume. Ether (150 ml.) was added to the solutionwhich was then cooled. The crystals were collected and recrystallizedfrom an isopropanol and ether mixture. Yield 31.6 g., M.P. 114- 117 C.

Example 3.N -o-chlorobenzyl-N -aminoguanidine HCl MethodA.l-o-chlorobenzyl-2-methylthiourea hydriodide, 10.0 g. (0.029 mole) wasdissolved in water (50 ml.) and hydrazine hydrate (1.0 g.) was added.The solution was heated to reflux for two hours and then evaporated todryness under reduced pressure. The substance was recrystallized from amixture of isopropanol and ether. Yield 6.6 g., M.P. 128-131" C.

This material was then treated with aqueous alkali, extracted withchloroform and the chloroform was then evaporated under reducedpressure. The residue was dissolved in ethanol and the solution pouredin cold ethereal hydrogen chloride. The product was recrystallized froman isopropanol and ether mixture. Yield 5.0 g., M.P. 170-172 C.

The free base of this material was obtained by treating the salt withaqueous alkali and extracting with chloroform. It was characterized bytaking an infra-red spectrum-the characteristic bands appearing at 1610cm.- and 1655 cm.-

Calculated for C I I N.;C1-HCl: N, 23.82%; Cl, 30.16%. Found: N, 23.48%;Cl, 29.96%.

Method B.2-methylthiosemicarbazide hydrochloride, 220.0 g. (0.78 mole)was dissolved in water (400 ml.) and o-chlorobenzylamine, 220.0 g. (0.78mole) was added. The solution was left standing at room temperature forforty-eight hours and then heated on a steam bath for four hours. Thesolution was cooled and the crystalline material collected andrecrystallized from methanol. Yield 127.5 g., M.P. 170172 C.

Calculated for C H N CI-HCI: N, 23.82%; Cl, 30.16%. Found: N, 23.48%;Cl, 29.96%.

Example 4.-N -o-chlorobenzyl-N -methyl-N -aminoguanidine HCl1-o-chlorobenzyl-2-methylthiourea hydroiodide, 10.0 g. (0.029 mole) wasdissolved in a mixture of water (50 ml.) and isopropanol (20 ml.) towhich methylhydrazine 1.54 g. (0.029 mole) was added. The reactionmixture was heated to reflux for sixteen hours and then evaporated todryness under reduced pressure. The residue was crystallized fromisopropanol. Yield 6.7 g., M.P. l30-132 C.

Example 5.-N -o-ch1orobenzyl-N -methyl-2-thiourea o-Chlorobenzylamine,35.4 g. (0.25 mole) was dissolved in water ml.) and methylisothiocyanate, 18.3 g. (0.25 mole) was added portionwise to thesolution which was stirred vigorously. The reaction mixture was heatedon a steam bath for one hour and then cooled. The water was decanted andthe gummy precipitate was crystallized from an isopropanol and methanolmixture. Yield 41.2 g., M.P. 126 C.

Calculated for C H ClN S: N, 15.6%. Found: N, 15.31%.

Example 6.N -o-chlorobenzyl-2,3-dimethylthiourea hydriodide N-o-chlorobenzyl-N -methyl-2-thiourea, 41.2 g. (0.19 mole) was dissolvedin acetone (200 ml.) and methyl iodide, 28.0 g. (0.19 mole) was added.The solution was stirred at room temperature for one hour. The productcrystallized on cooling the solution. The solid was collected andrecrystallized from isopropanol. Yield 60.3 g. M.P. 173-175 C.

Example 7.N -o-chlorobenzyl-N -methyl-N -dimethylaminoguanidine HCl N-o-chlorobenzyl 2,3 dimethylthiourea hydriodide, 10.0 g. (0.028 mole)was dissolved in water (50 ml.) and 1,1-dimethylhydrazine 1.7 g. (0.028mole) was added. The solution was heated to reflux for five hours andthen evaporated to dryness under reduced pressure. The material was thencrystallized from isopropanol. Yield 6.7 g., M.P. 130l34 C.

The infra-red spectrum of the free base of this material which wasisolated by the method described in Example 3, gave characteristic bandsat 3470 cm. and 1623 cm.-

The product was then converted to the corresponding hydrochloric acidsalt by the method described previously. M.P. 138-140? C.

Calculated for C H N Cl'HCl: Cl, 25.59%. Found: Cl, 25.86%.

Example 8.2-methylthiosemicarbazide hydrochloride Thiosemicarbazide,409.5 g. (4.5 moles) was dissolved in ethanol (1.125 ml.) and methylchloride (450 ml.) was added. The mixture was placed in a one-gallonpressure autoclave and heated to 80 C. for sixteen hours. The productwas then collected and recrystallized from ethanol. Yield 451.1 g., M.P.158-159 C.

Calculated for C H N S-HCl: Cl, 25.05%. Found: Cl, 25.57%.

Example 9.N -o-brmobenzyl-N -aminoguanidine HCl 2-methylthiosemicarbazide hydrochloride 7.61 g. (0.054 mole) wasdissolved in water (25 ml.) and o-bromo benzylamine, 10.0 g. (0.55 mole)was added. The solution was left standing at room temperature for twentyhours and then heated on a steam bath for four hours. The solution wascooled and the crystals collected. The product was recrystallized fromwater. Yield 2.2 g., M.P. 171-173 C.

The infra-red spectrum of the free base of this material gavecharacteristic bands at 1620 cmf 1445 cm.- and 1030 cmf Calculated for CH N Br-HCl: N, 20.04%; Cl, 12.67%. Found: N, 19.89%; Cl, 12.78%.

Example 10.N -o-methylbenzyl-N -aminoguanidine HClZ-methylthiosemicarbazide hydrochloride, 22.0 g. (0.156 mole) wasdissolved in water (25 ml.) and o-methylbenzylamine, 19.0 g. (0.156mole) was added. The solution was left standing at room temperature forseventy hours. The product was collected and recrystallized fromisopropanol. Yield 7.0 g., M.P. 147149 C.

The infra-red spectrum of the free base of this material hascharacteristic bands at 1625 cm- 1468 cm." and 1496 cmr Calculated for CH N -HCl: N, 16.52%. Found: N, 16.78%.

Example 1 1.N l-naphthylmethyl)-N -aminoguanidine HClZ-methylthiosemicarbazide hydriodide, 10.0 g. (0.043 mole) was dissolvedin water (25 ml.) and l-naphthylmethylamine, 6.8 g. (0.043 mole) wasadded. The solution was left standing at room temperature forforty-eight hours, and then heated on a steam bath for two hours. Thesolution was cooled and the crystals collected and recrystallized frommethanol. Yield 8.0 g., M.P. 183- 185 C.

The infra-red spectrum of the free base of this material gavecharacteristic bands at 1 625 cm.- and 1515 cm.-

This material was converted to the corresponding hydrochloric acid salt.Yield, 4.38 g., M.P. 151l53 C.

Calculated for C H N -HCl: Cl, 14.15%. Found: Cl, 14.16.

I claim:

1. N l-naphthylmethyl) -N -aminoguanidine.

2. N -(l-naphthylmethyD-N aminoguanidine hydrochloride.

References Cited Finnegan et al.: Journal Organic Chemistry, vol. 18,pages 780 and 786 (1953).

McKay et al.: Journal Med. Chem., vol. 6, No. 5, pages 587- (1963).

